Pyridyl-triazabicycles

ABSTRACT

The present invention provides a compound of formula I 
                         
having BACE1 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer&#39;s disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation Application of Ser. No. 15/314,718,filed on Nov. 29, 2016, which in turn is a National Stage Application ofPCT/EP2015/066600 filed Jul. 21, 2015, which claims priority fromEuropean Patent Application No. 14178503.0, filed on Jul. 25, 2014. Thepriority of both said PCT and European Patent Application are claimed.Each of prior mentioned applications is hereby incorporated by referenceherein in its entirety.

BACKGROUND ART

Alzheimer's disease (AD) is a neurodegenerative disorder of the centralnervous system and the leading cause of a progressive dementia in theelderly population. Its clinical symptoms are impairment of memory,cognition, temporal and local orientation, judgment and reasoning butalso severe emotional disturbances. There are currently no treatmentsavailable which can prevent the disease or its progression or stablyreverse its clinical symptoms. AD has become a major health problem inall societies with high life expectancies and also a significanteconomic burden for their health systems.

AD is characterized by 2 major pathologies in the central nervous system(CNS), the occurrence of amyloid plaques and neurofibrillar tangles(Hardy et al., The amyloid hypothesis of Alzheimer's disease: progressand problems on the road to therapeutics, Science. 2002 Jul. 19;297(5580):353-6, Selkoe, Cell biology of the amyloid beta-proteinprecursor and the mechanism of Alzheimer's disease, Annu Rev Cell Biol.1994; 10:373-403). Both pathologies are also commonly observed inpatients with Down's syndrome (trisomy 21), which also develop AD-likesymptoms in early life. Neurofibrillar tangles are intracellularaggregates of the microtubule-associated protein tau (MAPT). Amyloidplaques occur in the extracellular space; their principal components areAβ-peptides. The latter are a group of proteolytic fragments derivedfrom the β-amyloid precursor protein (APP) by a series of proteolyticcleavage steps. Several forms of APP have been identified of which themost abundant are proteins of 695, 751 and 770 amino acids length. Theyall arise from a single gene through differential splicing. TheAβ-peptides are derived from the same domain of the APP but differ attheir N- and C-termini, the main species are of 40 and 42 amino-acidlength. There are several lines of evidence which strongly suggest thataggregated Aβ-peptides are the essential molecules in the pathogenesisof AD: 1) amyloid plaques formed of Aβ-peptides are invariably part ofthe AD pathology; 2) Aβ-peptides are toxic for neurons; 3) in FamilialAlzheimer's Disease (FAD) the mutations in the disease genes APP, PSN1,PSN2 lead to increased levels of Aβ-peptides and early brainamyloidosis; 4) transgenic mice which express such FAD genes develop apathology which bears many resemblances to the human disease.Aβ-peptides are produced from APP through the sequential action of 2proteolytic enzymes termed β- and γ-secretase. β-Secretase cleaves firstin the extracellular domain of APP approximately 28 amino acids outsideof the trans-membrane domain (TM) to produce a C-terminal fragment ofAPP containing the TM- and the cytoplasmatic domain (CTFβ). CTFβ is thesubstrate for γ-secretase which cleaves at several adjacent positionswithin the TM to produce the Aβ peptides and the cytoplasmic fragment.The γ-secretase is a complex of at least 4 different proteins, itscatalytic subunit is very likely a presenilin protein (PSEN1, PSEN2).The β-secretase (BACE1, Asp2; BACE stands for β-site APP-cleavingenzyme) is an aspartyl protease which is anchored into the membrane by atransmembrane domain (Vassar et al., Beta-secretase cleavage ofAlzheimer's amyloid precursor protein by the transmembrane asparticprotease BACE, Science. 1999 Oct. 22; 286(5440):735). It is expressed inmany tissues of the human organism but its level is especially high inthe CNS. Genetic ablation of the BACE1 gene in mice has clearly shownthat its activity is essential for the processing of APP which leads tothe generation of Aβ-peptides, in the absence of BACE1 no Aβ-peptidesare produced (Luo et al., Mice deficient in BACE1, the Alzheimer'sbeta-secretase, have normal phenotype and abolished beta-amyloidgeneration, Nat Neurosci. 2001 March; 4(3):231-2, Roberds et al., BACEknockout mice are healthy despite lacking the primary beta-secretaseactivity in brain: implications for Alzheimer's disease therapeutics,Hum Mol Genet. 2001 Jun. 1; 10(12):1317-24). Mice which have beengenetically engineered to express the human APP gene and which formextensive amyloid plaques and Alzheimer's disease like pathologiesduring aging fail to do so when β-secretase activity is reduced bygenetic ablation of one of the BACE1 alleles (McConlogue et al., Partialreduction of BACE1 has dramatic effects on Alzheimer plaque and synapticpathology in APP Transgenic Mice. J Biol Chem. 2007 Sep. 7;282(36):26326). It is thus presumed that inhibitors of BACE1 activitycan be useful agents for therapeutic intervention in Alzheimer's disease(AD).

Furthermore, the formation, or formation and deposition, of β-amyloidpeptides in, on or around neurological tissue (e.g., the brain) areinhibited by the present compounds, i.e. inhibition of the Aβ-productionfrom APP or an APP fragment.

The present invention provides novel compounds of formula I, theirmanufacture, medicaments based on a compound in accordance with theinvention and their production as well as the use of compounds offormula I in the control or prevention of illnesses such as Alzheimer'sdisease.

FIELD OF THE INVENTION

The present invention provides triazabicycles having BACE1 inhibitoryproperties, their manufacture, pharmaceutical compositions containingthem and their use as therapeutically active substances.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I,

wherein the substituents and variables are as described below and in theclaims, or a pharmaceutically acceptable salt thereof.

The present compounds have Asp2 (β-secretase, BACE1 or Memapsin-2)inhibitory activity and may therefore be used in the therapeutic and/orprophylactic treatment of diseases and disorders characterized byelevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloidplaques and further deposits, particularly Alzheimer's disease.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula I and theirpharmaceutically acceptable salts thereof, the preparation of the abovementioned compounds, medicaments containing them and their manufactureas well as the use of the above mentioned compounds in the therapeuticand/or prophylactic treatment of diseases and disorders which areassociated with inhibition of BACE1, such as Alzheimer's disease.Furthermore, the formation, or formation and deposition, of β-amyloidplaques in, on or around neurological tissue (e.g., the brain) areinhibited by the present compounds by inhibiting the Aβ production fromAPP or an APP fragment.

The following definitions of the general terms used in the presentdescription apply irrespectively of whether the terms in question appearalone or in combination with other groups.

Unless otherwise stated, the following terms used in this Application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

The term “C₁₋₆-alkyl”, alone or in combination with other groups, standsfor a hydrocarbon radical which may be linear or branched, with singleor multiple branching, wherein the alkyl group in general comprises 1 to6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl, isopropyl(i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl(tert-butyl), isopentyl, 2-ethyl-propyl (2-methyl-propyl),1,2-dimethyl-propyl and the like. Particular “C₁₋₆-alkyl” are“C₁₋₃-alkyl”. Specific groups are methyl and ethyl. Most specific groupis methyl.

The term “halogen-C₁₋₆-alkyl”, alone or in combination with othergroups, refers to C₁₋₆-alkyl as defined herein, which is substituted byone or multiple halogen, particularly 1-5 halogen, more particularly 1-3halogen. Particular halogen is fluoro. Particular “halogen-C₁₋₆-alkyl”is fluoro-C₁₋₆-alkyl and a particular “halogen-C₁₋₃-alkyl” isfluoro-C₁₋₃-alkyl. Examples are trifluoromethyl, difluoromethyl,fluoromethyl and the like. A specific group is fluoromethyl.

The term “cyano”, alone or in combination with other groups, refers toN≡C—(NC—).

The term “halogen”, alone or in combination with other groups, denoteschloro (Cl), iodo (I), fluoro (F) and bromo (Br). Particular “halogen”are Cl, I and F. A specific group is F.

The term “heteroaryl”, alone or in combination with other groups, refersto an aromatic carbocyclic group of having a single 4 to 8 memberedring, in particular 5 to 8, or multiple condensed rings comprising 6 to14, in particular 6 to 10 ring atoms and containing 1, 2 or 3heteroatoms individually selected from N, O and S, in particular 1N or2N, in which group at least one heterocyclic ring is aromatic. Examplesof “heteroaryl” include benzofuryl, benzoimidazolyl, 1H-benzoimidazolyl,benzooxazinyl, benzoxazolyl, benzothiazinyl, benzothiazolyl,benzothienyl, benzotriazolyl, furyl, imidazolyl, indazolyl,1H-indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl,oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), 1H-pyrazolyl,pyrazolo[1,5-a]pyridinyl, pyridazinyl, pyridinyl, pyrimidinyl(pyrimidyl), pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl,triazolyl, 6,7-dihydro-5H-[1]pyrindinyl and the like. A particular“heteroaryl” is pyridinyl. A specific “heteroaryl” is pyridin-2-yl.

The term “aryl” denotes a monovalent aromatic carbocyclic mono- orbicyclic ring system comprising 6 to 10 carbon ring atoms. Examples ofaryl moieties include phenyl and naphthyl. Specific “aryl” is phenyl.

The term “pharmaceutically acceptable salts” refers to salts that aresuitable for use in contact with the tissues of humans and animals.Examples of suitable salts with inorganic and organic acids are, but arenot limited to acetic acid, citric acid, formic acid, fumaric acid,hydrochloric acid, lactic acid, maleic acid, malic acid,methane-sulfonic acid, nitric acid, phosphoric acid, p-toluenesulphonicacid, succinic acid, sulfuric acid (sulphuric acid), tartaric acid,trifluoroacetic acid and the like. Particular acids are formic acid,trifluoroacetic acid and hydrochloric acid. Specific acids arehydrochloric acid, trifluoroacetic acid and fumaric acid.

The terms “pharmaceutically acceptable carrier” and “pharmaceuticallyacceptable auxiliary substance” refer to carriers and auxiliarysubstances such as diluents or excipients that are compatible with theother ingredients of the formulation.

The term “pharmaceutical composition” encompasses a product comprisingspecified ingredients in pre-determined amounts or proportions, as wellas any product that results, directly or indirectly, from combiningspecified ingredients in specified amounts. Particularly it encompassesa product comprising one or more active ingredients, and an optionalcarrier comprising inert ingredients, as well as any product thatresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients.

The term “inhibitor” denotes a compound which competes with, reduces orprevents the binding of a particular ligand to particular receptor orwhich reduces or prevents the inhibition of the function of a particularprotein.

The term “half maximal inhibitory concentration” (IC₅₀) denotes theconcentration of a particular compound required for obtaining 50%inhibition of a biological process in vitro. IC₅₀ values can beconverted logarithmically to pIC₅₀ values (−log IC₅₀), in which highervalues indicate exponentially greater potency. The IC₅₀ value is not anabsolute value but depends on experimental conditions e.g.concentrations employed. The IC₅₀ value can be converted to an absoluteinhibition constant (Ki) using the Cheng-Prusoff equation (Biochem.Pharmacol. (1973) 22:3099). The term “inhibition constant” (Ki) denotesthe absolute binding affinity of a particular inhibitor to a receptor.It is measured using competition binding assays and is equal to theconcentration where the particular inhibitor would occupy 50% of thereceptors if no competing ligand (e.g. a radioligand) was present. Kivalues can be converted logarithmically to pKi values (−log Ki), inwhich higher values indicate exponentially greater potency.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The term “as defined herein” and “as described herein” when referring toa variable incorporates by reference the broad definition of thevariable as well as particularly, more particularly and mostparticularly definitions, if any.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

The term “aromatic” denotes the conventional idea of aromaticity asdefined in the literature, in particular in IUPAC—Compendium of ChemicalTerminology, 2nd, A. D. McNaught & A. Wilkinson (Eds). BlackwellScientific Publications, Oxford (1997).

The term “pharmaceutically acceptable excipient” denotes any ingredienthaving no therapeutic activity and being non-toxic such asdisintegrators, binders, fillers, solvents, buffers, tonicity agents,stabilizers, antioxidants, surfactants or lubricants used in formulatingpharmaceutical products.

Whenever a chiral carbon is present in a chemical structure, it isintended that all stereoisomers associated with that chiral carbon areencompassed by the structure as pure stereoisomers as well as mixturesthereof.

The invention also provides pharmaceutical compositions, methods ofusing, and methods of preparing the aforementioned compounds.

All separate embodiments may be combined.

One embodiment of the invention provides a compound of formula I,

whereinR¹ is selected from the group consisting of

-   -   i) aryl,    -   ii) aryl, substituted by 1-3 substituents individually selected        from cyano, C₁₋₆-alkyl, halogen-C₁₋₆-alkyl and halogen    -   iii) heteroaryl,    -   iv) heteroaryl, substituted by 1-3 substituents individually        selected from cyano, C₁₋₆-alkyl, halogen-C₁₋₆-alkyl and halogen,        and        R² together with R⁴ is selected from the group consisting of    -   i) —(CH₂)_(x)-, wherein x=3 or 4; substituted by 1 or 2        halogen-C₁₋₆-alkyl, and    -   ii) —(CH₂)—(CY₂)_(z)—(CH₂)—, wherein each individual Y=H or F        and z=1 or 2;        R³ is selected from the group consisting of    -   i) C₁₋₆-alkyl, and    -   ii) halogen-C₁₋₆-alkyl;        or pharmaceutically acceptable salts thereof.

A certain embodiment of this invention relates to a compound of formulaI as described herein, wherein

R¹ is selected from the group consisting of

-   -   i) aryl,    -   ii) aryl, substituted by 1-3 substituents individually selected        from cyano, C₁₋₆-alkyl, halogen-C₁₋₆-alkyl and halogen    -   iii) heteroaryl,    -   iv) heteroaryl, substituted by 1-3 substituents individually        selected from cyano, C₁₋₆-alkyl, halogen-C₁₋₆-alkyl and halogen,        and        R² together with R⁴ is —(CH₂)_(x)—, wherein x=3 or 4;        R³ is selected from the group consisting of    -   i) C₁₋₆-alkyl, and    -   ii) halogen-C₁₋₆-alkyl;        or pharmaceutically acceptable salts thereof.

A certain embodiment of this invention relates to a compound of formulaI as described herein, which is of formula Ia, wherein R¹, R², R⁴ and R⁴are as described herein.

A certain embodiment of this invention relates to a compound of formulaI as described herein, which is of formula Ic, wherein R¹, R², R⁴ and R⁴are as described herein.

A certain embodiment of this invention relates to a compound of formulaI as described herein, which is of formula Id, wherein R¹, R², R⁴ and R⁴are as described herein.

A certain embodiment of this invention relates to a compound of formulaI as described herein, wherein R¹ is heteroaryl, substituted by 1-2substituents individually selected from cyano and C₁₋₆-alkyl.

A certain embodiment of this invention relates to a compound of formulaI as described herein, wherein R¹ is pyridyl, substituted by 1-2substituents individually selected from cyano and C₁₋₆-alkyl.

A certain embodiment of this invention relates to a compound of formulaI as described herein, wherein R¹ is 5-cyano-3-methyl-pyridin-2yl or5-cyano-pyridin-2yl.

A certain embodiment of this invention relates to a compound of formulaI as described herein, wherein R² and R⁴ together are—(CH₂)—(CY₂)_(z)—(CH₂)—, Y is H and z is 2.

A certain embodiment of this invention relates to a compound of formulaI as described herein, wherein R³ is methyl.

A certain embodiment of this invention relates to a compound of formulaI as described herein, wherein R³ is —CH₂F.

A certain embodiment of this invention relates to a compound of formulaI as described herein that is selected from the group consisting of

-   5-Cyano-pyridine-2-carboxylic acid    [6-((3R,4aR)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amid,-   5-Cyano-pyridine-2-carboxylic acid    [6-((3R,4aS)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amide,-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [6-((3R,4aS)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amide,-   N-[6-[(1S,10S)-8-Amino-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide,    and-   N-[6-[(1R,10S)-8-Amino-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide.

A certain embodiment of the invention relates to a process comprisesreacting a compound of formula XI′ with a compound of formula XII′ to acompound of formula I.

wherein R¹, R², R³ and R⁴ are as defined herein.

A certain embodiment of the invention provides a compound of formula Ias described herein whenever prepared by a process as described herein.

A certain embodiment of the invention provides a compound of formula Ias described herein for use as therapeutically active substance.

A certain embodiment of the invention provides a compound of formula Ias described herein for the use as inhibitor of BACE1 activity.

A certain embodiment of the invention provides a compound of formula Ias described herein for the use as therapeutically active substance forthe therapeutic and/or prophylactic treatment of diseases and disorderscharacterized by elevated β-amyloid levels and/or β-amyloid oligomersand/or β-amyloid plaques and further deposits or Alzheimer's disease.

A certain embodiment of the invention provides a compound of formula Ias described herein for the use as therapeutically active substance forthe therapeutic and/or prophylactic treatment of Alzheimer's disease.

A certain embodiment of the invention provides a pharmaceuticalcomposition comprising a compound of formula I as described herein and apharmaceutically acceptable carrier and/or a pharmaceutically acceptableauxiliary substance.

A certain embodiment of the invention provides the use of a compound offormula I as described herein for the manufacture of a medicament forthe use in inhibition of BACE1 activity.

A certain embodiment of the invention provides the use of a compound offormula I as described herein for the manufacture of a medicament forthe therapeutic and/or prophylactic treatment of diseases and disorderscharacterized by elevated β-amyloid levels and/or β-amyloid oligomersand/or β-amyloid plaques and further deposits or Alzheimer's disease.

A certain embodiment of the invention provides the use of a compound offormula I as described herein for the manufacture of a medicament forthe therapeutic and/or prophylactic treatment of Alzheimer's disease.

A certain embodiment of the invention provides the use of a compound offormula I as described herein for the manufacture of a medicament forthe therapeutic and/or prophylactic treatment of Alzheimer's disease.

A certain embodiment of the invention provides a compound of formula Ias described herein for the use in inhibition of BACE1 activity.

A certain embodiment of the invention provides a compound of formula Ias described herein for the use in the therapeutic and/or prophylactictreatment of diseases and disorders characterized by elevated β-amyloidlevels and/or β-amyloid oligomers and/or β-amyloid plaques and furtherdeposits or Alzheimer's disease.

A certain embodiment of the invention provides a compound of formula Ias described herein for the use in the therapeutic and/or prophylactictreatment of Alzheimer's disease.

A certain embodiment of the invention provides a method for the use ininhibition of BACE1 activity, particularly for the therapeutic and/orprophylactic treatment of diseases and disorders characterized byelevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloidplaques and further deposits or Alzheimer's disease, which methodcomprises administering compound of formula I as described herein to ahuman being or animal.

A certain embodiment of the invention provides a method for the use inthe therapeutic and/or prophylactic treatment of Alzheimer's disease,which method comprises administering a compound of formula I asdescribed herein to a human being or animal.

Furthermore, the invention includes all optical isomers, i.e.diastereoisomers, diastereomeric mixtures, racemic mixtures, all theircorresponding enantiomers and/or tautomers as well as their solvates ofthe compounds of formula I.

The skilled person in the art will recognize that the compounds offormula I can exist in tautomeric form

All tautomeric forms are encompassed in the present invention.

The compounds of formula I may contain one or more asymmetric centersand can therefore occur as racemates, racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers.Additional asymmetric centers may be present depending upon the natureof the various substituents on the molecule. Each such asymmetric centerwill independently produce two optical isomers and it is intended thatall of the possible optical isomers and diastereomers in mixtures and aspure or partially purified compounds are included within this invention.The present invention is meant to encompass all such isomeric forms ofthese compounds. The independent syntheses of these diastereomers ortheir chromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography.

In the embodiments, where optically pure enantiomers are provided,optically pure enantiomer means that the compound contains >90% of thedesired isomer by weight, particularly >95% of the desired isomer byweight, or more particularly >99% of the desired isomer by weight, saidweight percent based upon the total weight of the isomer(s) of thecompound. Chirally pure or chirally enriched compounds may be preparedby chirally selective synthesis or by separation of enantiomers. Theseparation of enantiomers may be carried out on the final product oralternatively on a suitable intermediate.

The compounds of formula I can be prepared through a number of syntheticroutes for example as illustrated in scheme 1. The preparation ofcompounds of formula I of the present invention may be carried out insequential or convergent synthetic routes. Syntheses of the compounds ofthe invention are shown in the following scheme 1. The skills requiredfor carrying out the reaction and purification of the resulting productsare known to those skilled in the art. The substituents and indices usedin the following description of the processes have the significancegiven herein before unless indicated to the contrary.

In more detail, the compounds of formula I can be manufactured by themethods given below, by the methods given in the examples or byanalogous methods. Appropriate reaction conditions for the individualreaction steps are known to a person skilled in the art. The reactionsequence is not limited to the one displayed in schemes described below,however, depending on the starting materials and their respectivereactivity the sequence of reaction steps can be freely altered.Starting materials are either commercially available or can be preparedby methods analogous to the methods given below, by methods described inreferences cited in the description or in the examples, or by methodsknown in the art.

The compounds of formula I described in the scheme 1 can be isolated andpurified by methods known to those skilled in the art, such as but notlimited to ion exchange chromatography, solid phase extraction,liquid-liquid extraction, silica chromatography, crystallization andpreparative HPLC.

In more detail, compounds of formula I according to the presentinvention can be prepared by the methods and procedures given below.Some typical procedures for the preparation of compounds of formula Iare illustrated in scheme 1.

Non-commercial aryl ketones of general formula A3 can be synthesizedfrom the silyl protected pyridine A2 prepared from pyridine A1 byreaction with a strong base, e.g. LDA and an alkylchlorosilane,preferably triethylchlorosilane in an inert aprotic solvents such astetrahydrofuran or diethyl ether. The protected pyridine A2 can then bereacted again with a strong base, e.g. LDA and an amide, e.g. anacetamide for R³=Me, preferably N,N-dimethylacetamide, or LDA and anester, e.g. ethyl difluoroacetate for R³═CHF₂ or methyl fluoroacetatefor R³═CH₂F, in an inert aprotic solvents such as tetrahydrofuran ordiethyl ether to give the desired aryl ketone A3.

Sulfinyl imines of formula A4 can be prepared in analogy to T. P. Tang &J. A. Ellman, J. Org. Chem. 1999, 64, 12, by condensation of an arylketone of formula B3 and a sulfinamide, e.g. an alkyl sulfinamide, mostparticularly (R)-tert-butylsulfinamide or (S)-tert-butylsulfinamide, inthe presence of a Lewis acid such as e.g. a titanium(IV)alkoxide, moreparticularly titanium(IV)ethoxide, in a solvent such as an ether, e.g.diethyl ether or more particularly tetrahydrofuran.

The conversion of sulfinyl imines of formula A4 tosulfonamides-sulfonimidamides of formula A5 can proceedstereoselectively by the chiral directing group as described by Tang &Ellman. The sulfinyl imines of formula A4 can be reacted in an additionreaction with a lithiated sulfonimidamide, generated from asulfonimidamide of formula B4 and a base such as n-butyllithium, lithiumhexamethyldisilazid or LDA, in a solvent such as an ether, e.g. diethylether or more particularly tetrahydrofuran, at low temperatures,preferably −78° C.

The conversion of the sulfonamides-sulfonimidamides of formula A5 whereR′=SiEt₃ to the desilylated sulfonamides-sulfonimidamides of formula A6where R′=H can be effected with tetrabutylammonium fluoride orpreferably potassium fluoride in the presence of an acid e.g. aceticacid in an ether or an amide preferably in a mixture of THF anddimethylformamide at ambient to elevated temperature, particularly at 23to 40° C.

Hydrolysis of the chiral directing group and the 2,4-dimethoxybenzylgroup (DMB) of sulfonamides-sulfonimidamides of formula A6 where R′=H togive the amino-sulfonimidamides of formula A7 can be accomplished byfirst treatment with a mineral acid, e.g. sulfuric acid or particularlyhydrochloric acid, in a solvent such as an ether, e.g. diethyl ether,tetrahydrofuran or more particularly 1,4-dioxane, and second bytreatment with a strong organic acid, e.g. trifluoroacetic acid, whereboth steps are preferably conducted at ambient temperature.

Reaction of the amino sulfonimidamides of formula A7 with anisothiocyanate such as benzoylisothiocyanate in solvents such as ethylacetate, tetrahydrofuran or acetonitrile at temperatures between 0° C.and 80° C., preferably 23° C., affords the thiourea sulfonimidamides offormula A8.

The thiourea sulfonimidamides of formula A8 can be cyclized to theN-benzoylated amidine sulfonimidamides of formula A9 by dehydrationthrough reaction with a carbodiimide, like e.g.dicyclohexylcarbodiimide, diisopropylcarbodiimide orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl),preferably EDC HCl, in solvents such as ethyl acetate, tetrahydrofuranor acetonitrile, preferably acetonitrile, at temperatures between 23° C.and 100° C., preferably 80° C.

The switch of protecting groups from the N-benzoylated amidinesulfonimidamides of formula A9 to the N-tert-butoxycarbonylated amidinesulfonimidamides of formula A10 can be achieved in a two step procedureby first reaction with di-tert-butyldicarbonate (Boc₂O) in the presenceof an amine base such as triethylamine or N-ethyl-N,N-diisopropylamine,in a solvent such as dichlormethane, tetrahydrofuran or acetonitrile, attemperatures between 0° C. and 40° C., preferably 23° C., to give thedoubly acylated amidine sulfonimidamides of formula A18, and secondselective removal of the benzoyl group by reaction of the doublyacylated amidine sulfonimidamides with an amine nucleophile, like e.g.diethylamine, dimethylamine or ammonia, preferably ammonia, in a solventsuch as dichloromethane or tetrahydrofuran, preferably tetrahydrofuran,at temperatures between 0° C. and 40° C., preferably 23° C.

The conversion of the bromo group in formula A10 to the amine group informula A11 can be performed by reaction with an azide, in particularsodium azide and a cooper (I) halide in particular copper (I) iodide inthe presence of L-ascorbate and an alkyl-1,2-diamine in particulartrans-N,N′-dimethylcyclohexane-1,2-diamine in a protic solvent such asan alcohol in particular ethanol and water at elevated temperaturepreferably approximately 70° C.

The coupling of the aromatic amine A11 with carboxylic acids (R¹—CO₂H)to give amides of formula A12 can be effected with T3P in an aproticsolvent such as EtOAc at ambient temperature; or alternatively thecarboxylic acids (R¹—CO₂H) can be activated by using reagents such asoxalyl chloride or 1-chloro-N,N,2-trimethyl-1-propenylamine (Ghosez'sreagent, CAS-no. 26189-59-3) in a chlorinated solvent such asdichloromethane at 0° C. followed by reaction with the aromatic amineA11 in the presence of an amine base such as triethylamine ordiisopropylethylamine at 0° C. to ambient temperature.

The cleavage of the protecting tert-butoxy carbonyl groups in compoundsof formula A12 to produce compounds of general formula I can be effectedby acid, such as trifluoroacetic acid, in inert solvents, such asdichloromethane, at temperatures between 0° C. and ambient temperature.

The methanesulfinyl chloride of formula B2 can be prepared by treatmentof commercially available dimethyldisulfide of formula B1 with sulfurylchloride and acetic acid at temperatures between −30° C. and 35° C. asdescribed by Youn, Joo-Hack; Herrmann, Rudolf in Tetrahedron Letters1986, 27(13), 1493-1494. The crude methanesulfinyl chloride of formulaB2 can be purified by distillation or used directly in the next step toproduce the sulfinamides of formula B3 which is achieved by simplereaction with an excess of an amine R²—NH₂ or mixtures of an amineR²—NH₂ with an amine base, such as triethylamine orN-ethyl-N,N-diisopropylamine, in a solvent such as dichlormethane ortetrahydrofuran, at temperatures starting as low as −78° C. and warmingup to 0° C. or 23° C.

The sulfonimidamides of formula B4 can be prepared from the sulfinamidesof formula B3 by reaction with a chlorinating reagent such asN-chlorosuccinamide or tert-butyl hypochlorite, preferably tert-butylhypochlorite, in an inert solvent such as acetonitrile, tetrahydrofuranor dichloromethane, preferably dichloromethane, at temperatures startingas low as −78° C. and warming up to 0° C., to produce the intermediatesulfonimidoyl chlorides followed by reaction with an excess of an amineR⁴-NHDMB or mixtures of an amine R⁴-NHDMB with an amine base, such astriethylamine or N-ethyl-N,N-diisopropylamine at temperatures startingas low as −78° C. and warming up to 0° C. or 23° C. The amines R⁴-NHDMBare generally prepared by a reductive amination of an amine R⁴—NH₂ with2,4-dimethoxybenzaldehyde by methods known to someone skilled in theart.

The corresponding pharmaceutically acceptable salts with acids can beobtained by standard methods known to the person skilled in the art,e.g. by dissolving the compound of formula I in a suitable solvent suchas e.g. dioxane or tetrahydrofuran and adding an appropriate amount ofthe corresponding acid. The products can usually be isolated byfiltration or by chromatography. The conversion of a compound of formulaI into a pharmaceutically acceptable salt with a base can be carried outby treatment of such a compound with such a base. One possible method toform such a salt is e.g. by addition of 1/n equivalents of a basic saltsuch as e.g. M(OH)_(n), wherein M=metal or ammonium cation and n=numberof hydroxide anions, to a solution of the compound in a suitable solvent(e.g. ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) andto remove the solvent by evaporation or lyophilisation. Particular saltsare hydrochloride, formate and trifluoroacetate. Specific ishydrochloride.

Insofar as their preparation is not described in the examples, thecompounds of formula I as well as all intermediate products can beprepared according to analogous methods or according to the methods setforth herein. Starting materials are commercially available, known inthe art or can be prepared by methods known in the art or in analogythereto.

It will be appreciated that the compounds of general formula I in thisinvention may be derivatised at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.

Pharmacological Tests

The compounds of formula I and their pharmaceutically acceptable saltspossess valuable pharmacological properties. It has been found that thecompounds of the present invention are associated with inhibition ofBACE1 activity. The compounds were investigated in accordance with thetest given hereinafter.

Cellular Aβ-lowering Assay:

The Abeta 40 AlphaLISA Assay can be used. The HEK293 APP cells wereseeded in 96 well Microtiter plates in cell culture medium (Iscove's,plus 10% (v/v) fetal bovine serum, penicillin/streptomycin) to about 80%confluency and the compounds were added at a 3× concentration in 1/3volume of culture medium (final DMSO concentration was kept at 1% v/v).After 18-20 hrs incubation at 37° C. and 5% CO₂ in a humidifiedincubator, the culture supernatants were harvested for the determinationof Aβ 40 concentrations using Perkin-Elmer Human Amyloid beta 1-40 (highspecificity) Kit (Cat# AL275C).

In a Perkin-Elmer White Optiplate-384 (Cat#6007290), 2 μl culturesupernatants were combined with 2 μl of a 10×AlphaLISA Anti-hAβAcceptorbeads+Biotinylated Antibody Anti-Aβ 1-40 Mix (50 μg/mL/5 nM). After 1hour room temperature incubation, 16 μl of a 1.25× preparation ofStreptavidin (SA) Donor beads (25 μg/mL) were added and incubated for 30minutes in the Dark. Light Emission at 615 nm was then recorded usingEnVision-Alpha Reader. Levels of Aβ 40 in the culture supernatants werecalculated as percentage of maximum signal (cells treated with 1% DMSOwithout inhibitor). The IC₅₀ values were calculated using the ExcelXLfit software.

TABLE 1 IC₅₀ values BACE1 Exam. Structure IC₅₀ [μM] 1

0.086 2

0.049 3

0.036 4

0.096 5

0.028Pharmaceutical Compositions

The compounds of formula I and the pharmaceutically acceptable salts canbe used as therapeutically active substances, e.g. in the form ofpharmaceutical preparations. The pharmaceutical preparations can beadministered orally, e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatin capsules, solutions, emulsions orsuspensions. The administration can, however, also be effected rectally,e.g. in the form of suppositories, or parenterally, e.g. in the form ofinjection solutions.

The compounds of formula I and the pharmaceutically acceptable saltsthereof can be processed with pharmaceutically inert, inorganic ororganic carriers for the production of pharmaceutical preparations.Lactose, corn starch or derivatives thereof, talc, stearic acids or itssalts and the like can be used, for example, as such carriers fortablets, coated tablets, dragées and hard gelatin capsules. Suitablecarriers for soft gelatin capsules are, for example, vegetable oils,waxes, fats, semi-solid and liquid polyols and the like. Depending onthe nature of the active substance no carriers are however usuallyrequired in the case of soft gelatin capsules. Suitable carriers for theproduction of solutions and syrups are, for example, water, polyols,glycerol, vegetable oil and the like. Suitable carriers forsuppositories are, for example, natural or hardened oils, waxes, fats,semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain pharmaceuticallyacceptable auxiliary substances such as preservatives, solubilizers,stabilizers, wetting agents, emulsifiers, sweeteners, colorants,flavorants, salts for varying the osmotic pressure, buffers, maskingagents or antioxidants. They can also contain still othertherapeutically valuable substances.

Medicaments containing a compound of formula I or a pharmaceuticallyacceptable salt thereof and a therapeutically inert carrier are alsoprovided by the present invention, as is a process for their production,which comprises bringing one or more compounds of formula I and/orpharmaceutically acceptable salts thereof and, if desired, one or moreother therapeutically valuable substances into a galenicaladministration form together with one or more therapeutically inertcarriers.

The dosage can vary within wide limits and will, of course, have to beadjusted to the individual requirements in each particular case. In thecase of oral administration the dosage for adults can vary from about0.01 mg to about 1000 mg per day of a compound of general formula I orof the corresponding amount of a pharmaceutically acceptable saltthereof. The daily dosage may be administered as single dose or individed doses and, in addition, the upper limit can also be exceededwhen this is found to be indicated.

The following examples illustrate the present invention without limitingit, but serve merely as representative thereof. The pharmaceuticalpreparations conveniently contain about 1-500 mg, particularly 1-100 mg,of a compound of formula I. Examples of compositions according to theinvention are:

EXAMPLE A

Tablets of the following composition are manufactured in the usualmanner:

TABLE 2 possible tablet composition mg/tablet ingredient 5 25 100 500Compound of formula I 5 25 100 500 Lactose Anhydrous DTG 125 105 30 150Sta-Rx 1500 6 6 6 60 Microcrystalline Cellulose 30 30 30 450 MagnesiumStearate 1 1 1 1 Total 167 167 167 831Manufacturing Procedure1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.2. Dry the granules at 50° C.3. Pass the granules through suitable milling equipment.4. Add ingredient 5 and mix for three minutes; compress on a suitablepress.

EXAMPLE B-1

Capsules of the following composition are manufactured:

TABLE 3 possible capsule ingredient composition mg/capsule ingredient 525 100 500 Compound of formula I 5 25 100 500 Hydrous Lactose 159 123148 — Corn Starch 25 35 40 70 Talk 10 15 10 25 Magnesium Stearate 1 2 25 Total 200 200 300 600Manufacturing Procedure1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.2. Add ingredients 4 and 5 and mix for 3 minutes.3. Fill into a suitable capsule.

The compound of formula I, lactose and corn starch are firstly mixed ina mixer and then in a comminuting machine. The mixture is returned tothe mixer; the talc is added thereto and mixed thoroughly. The mixtureis filled by machine into suitable capsules, e.g. hard gelatin capsules.

EXAMPLE B-2

Soft Gelatin Capsules of the following composition are manufactured:

TABLE 4 possible soft gelatin capsule ingredient composition ingredientmg/capsule Compound of formula I 5 Yellow wax 8 Hydrogenated Soya beanoil 8 Partially hydrogenated plant oils 34 Soya bean oil 110 Total 165

TABLE 5 possible soft gelatin capsule composition ingredient mg/capsuleGelatin 75 Glycerol 85% 32 Karion 83 8 (dry matter) Titan dioxide 0.4Iron oxide yellow 1.1 Total 116.5Manufacturing Procedure

The compound of formula I is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

EXAMPLE C

Suppositories of the following composition are manufactured:

TABLE 6 possible suppository composition ingredient mg/supp. Compound offormula I 15 Suppository mass 1285 Total 1300Manufacturing Procedure

The suppository mass is melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C. Thereupon, the finely powdered compoundof formula I is added thereto and stirred until it has dispersedcompletely. The mixture is poured into suppository moulds of suitablesize, left to cool; the suppositories are then removed from the mouldsand packed individually in wax paper or metal foil.

EXAMPLE D

Injection solutions of the following composition are manufactured:

TABLE 7 possible injection solution composition ingredient mg/injectionsolution. Compound of formula I 3 Polyethylene Glycol 400 150 aceticacid q.s. ad pH 5.0 water for injection solutions ad 1.0 mlManufacturing Procedure

The compound of formula I is dissolved in a mixture of PolyethyleneGlycol 400 and water for injection (part). The pH is adjusted to 5.0 byacetic acid. The volume is adjusted to 1.0 ml by addition of theresidual amount of water. The solution is filtered, filled into vialsusing an appropriate overage and sterilized.

EXAMPLE E

Sachets of the following composition are manufactured:

TABLE 8 possible sachet composition ingredient mg/sachet Compound offormula I 50 Lactose, fine powder 1015 Microcrystalline cellulose(AVICEL PH 102) 1400 Sodium carboxymethyl cellulose 14Polyvinylpyrrolidon K 30 10 Magnesium stearate 10 Flavoring additives 1Total 2500Manufacturing Procedure

The compound of formula I is mixed with lactose, microcrystallinecellulose and sodium carboxymethyl cellulose and granulated with amixture of polyvinylpyrrolidone in water. The granulate is mixed withmagnesium stearate and the flavoring additives and filled into sachets.

Experimental Part

The following examples are provided for illustration of the invention.They should not be considered as limiting the scope of the invention,but merely as being representative thereof.

General

NMR: ¹H NMR spectra were recorded on a Bruker AC-300 spectrometer at 25°C. with TMS (tetramethylsilane) or residual ¹H of the given deuteratedsolvents as internal standards.

MS: Mass spectra (MS) were measured either with ion spray positive ornegative (ISP or ISN) method on a Perkin-Elmer SCIEX API 300 or withelectron impact method (EI, 70 eV) on a Finnigan MAT SSQ 7000spectrometer.

LC-MS (ESI, positive or negative ion) data were recorded on WatersUPLC-MS Systems equipped with Waters Acquity, a CTC PAL auto sampler anda Waters SQD single quadrupole mass spectrometer using ES ionizationmodes (positive and/or negative). The separation was achieved on aZorbax Eclipse Plus C18 1.7 μm 2.1×30 mm column at 50° C.; A=0.01%formic acid in water, B=acetonitrile at flow 1; gradient: 0 min 3% B,0.2 min 3% B, 2 min 97% B, 1.7 min 97% B, 2.0 min 97% B. The injectionvolume was 2 μL. MS (ESI, positive or negative ion): FIA (flow injectionanalysis)-MS were recorded on an AppliedBiosystem API150 massspectrometer. Sample introduction was made with a CTC PAL auto samplerand a Shimadzu LC-10ADVP Pump. The samples were directly flushed to theESI source of the mass spectrometer with a flow 50 μL/min of a mixtureof acetonitrile and 10 mM ammonium acetate (1:1) without a column. Theinjection volume was 2 μL.

General

Abbreviations

Boc=tert-Butoxycarbonyl, DCM=dichloromethane,EDC.HCl=N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride,EtOAc=Ethyl acetate, HCl=hydrogen chloride, HPLC=high performance liquidchromatography, LDA=lithium diisopropylamide, MS=mass spectrum,THF=tetrahydrofuran, andT3P=2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide.

NMR: ¹H NMR spectra were recorded on a Bruker AC-300 spectrometer at 25°C. with TMS (tetramethylsilane) or residual ¹H of the given deuteratedsolvents as internal standards.

MS: Mass spectra (MS) were measured either with ion spray positive ornegative (ISP or ISN) method on a Perkin-Elmer SCIEX API 300 or withelectron impact method (EI, 70 eV) on a Finnigan MAT SSQ 7000spectrometer.

Synthesis of the Intermediate Sulfinyl Imines A4 A4a (R³=Me):(R,E)-N-(1-(6-Bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide

To a solution of1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)ethanone, preparedaccording to Badiger, S. et al., int. patent application WO2012095469A1, (8.13 g) in THF (59 ml) was added subsequently at 22° C.(R)-(+)-tert-butylsulfinamide (3.26 g) and titanium(IV)ethoxide (11.2 g)and the solution was stirred at 60° C. for 6 h. The mixture was cooledto 22° C., treated with brine, the suspension was stirred for 10 min andfiltered over dicalite. The layers were separated, the aqueous layer wasextracted with ethyl acetate, the combined organic layers were washedwith water, dried and evaporated. The residue was purified by flashchromatography (SiO₂, n-heptane/EtOAc, 5:1) to give the title compound(7.5 g, 70%) as a yellow oil. MS (ESI): m/z=435.3, 437.3 [M+H]⁺.

A4b (R³=CH₂F):(R,E)-N-(1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide

Step 1: To a solution of diisopropylamine (3.55 g, 5.00 ml, 35.1 mmol,Eq: 1.1) in tetrahydrofuran (80 ml) was added dropwise at −40° C. underinert atmosphere n-BuLi (1.6 M in hexane) (21.9 ml, 35.1 mmol, Eq: 1.1).After complete addition the solution was allowed to warm to −10° C. andstirred for 10 minutes. The mixture was again cooled to −78° C. and asolution of 2-bromo-5-fluoro-4-(triethylsilyl)pyridine (9.26 g, 31.9mmol, Eq: 1.00), prepared according to Badiger, S. et al., int. patentapplication WO 2012095469A1, in tetrahydrofuran (20 ml) was addeddropwise while internal temperature was held below −70° C. The yellowsolution was stirred at −78° C. for 1 hour while color changed to darkred. Then was added dropwise methyl 2-fluoroacetate (3.52 g, 38.3 mmol,Eq: 1.2). The mixture was warmed to −10° C. within 30 min and thenquenched by pouring the mixture onto sat. NH₄Cl/1 M HCl. The mixture wasextracted twice with EtOAc, dried over Na₂SO₄, filtered and evaporatedto give1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-fluoroethanone(11.03 g, 31.5 mmol, 98.7% yield) as a yellow oil which was used withoutfurther purification. MS (ESI): m/z=350.3, 352.3 [M+H]⁺.

Step 2: To a solution of1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-fluoroethanone(10.98 g, 28.2 mmol, Eq: 1.00) in THF (100 ml) was added at 23° C.(R)-(+)-2-methylpropane-2-sulfinamide (6.28 g, 50.8 mmol, Eq: 1.8) andtitanium(IV) ethoxide (29.0 g, 26.8 ml, 127 mmol, Eq: 4.5). The dark redreaction solution was stirred at 23° C. for 16 hours. 200 ml of waterand 200 ml of ethyl acetate were added to the reaction mixture. Afterstirring for 10 min the slurry was filtered off through a pad ofdicalite. The organic layer was separated and washed with water andbrine. The aequous layers were reextracted with ethyl acetate (100 ml).The combined organic extracts were dried over Na₂SO₄, filtered andevaporated to give a brown oil. The residue was purified by flashchromatography (70 g silica gel, 0-30% EtOAc in heptane) to give(R,E)-N-(1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide(7.88 g, 17.4 mmol, 61.6% yield) as a yellow oil. MS (ESI): m/z=453.3,455.6 [M+H]⁺.

A4c (R³=CHF₂):(S,E)-N-(1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide

Step 1: A solution of diisopropylamine (3.45 g, 4.86 ml, 34.1 mmol, Eq:1.10) and THF (90 ml) was cooled to −78° C. n-BuLi (1.6 M in hexane)(21.3 ml, 34.1 mmol, Eq: 1.10) was added dropwise. After completeaddition the solution was allowed to warm to 10° C. and stirred for 20minutes. The mixture was again cooled to −78° C.2-bromo-5-fluoro-4-(triethylsilyl)pyridine (9 g, 31.0 mmol, Eq: 1.00),prepared according to Badiger, S. et al., int. patent application WO2012095469A1, was added dropwise at max. −60° C. The yellow solution wasstirred at −78° C. for 2 hours while color changed to dark red. Thenethyl difluoroacetate (4.62 g, 3.72 ml, 37.2 mmol, Eq: 1.20) was addeddropwise. The mixture was warmed to −10° C. and then quenched by pouringthe mixture onto 1 M HCl. The mixture was extracted with EtOAc twice,dried on Na₂SO₄, filtered and evaporated. The residue was purified byflash chromatography (silica gel, 70 g, 0-30% EtOAc in heptane) to give1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2,2-difluoroethanone(3.75 g, 10.2 mmol, 32.8% yield) as a light brown oil.

Step 2: To a solution of1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2,2-difluoroethanone(3.75 g, 10.2 mmol, Eq: 1.00) in tetrahydrofuran (40.7 ml) was added atrt (S)-(−)-2-methylpropane-2-sulfinamide (2.22 g, 18.3 mmol, Eq: 1.8)and titanium(IV) ethoxide (6.97 g, 6.33 ml, 30.5 mmol, Eq: 3.0). Thereaction mixture was stirred at 23° C. for 16 hours and 3 hours at 60°C. 100 ml of water and 100 ml of ethyl acetate were added to thereaction mixture. After stirring for 10 min the slurry was filtered offthrough a pad of dicalite. The organic layer was separated and washedwith water and brine. The aequous layers were reextracted with ethylacetate (100 ml). The combined organic extracts were dried over Na₂SO₄,filtered and evaporated to give a brown oil. The residue was purified bychromatography (silica gel, 50 g, 0-30% EtOAc in heptane) to give(S,E)-N-(1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide(2.73 g, 5.79 mmol, 56.9% yield) as a yellow oil. MS (ESI): m/z=471.1,473.3 [M+H]⁺.

Synthesis of the Intermediate sulfinamide B3 B3a:N-allylmethanesulfinamide

Step 1: A solution of 1,2-dimethyldisulfane (79.6 g, 75 ml, 846 mmol,Eq: 1.00) in acetic acid (102 g, 96.7 ml, 1.69 mol, Eq: 2) was cooled to−20° C. (mixture solidified), start dropwise addition of sulfuryldichloride (354 g, 212 ml, 2.62 mol, Eq: 3.1) (after 1-2 ml it forms anorange solution). After complete addition stirring was continued at −20°C. for 1.5 h. Removed the cooling bath and let the reaction reachambient temperature (gas evolution). Stirring was continued at 35° C.for 1 h. Removed the acetyl chloride at 40° C. and 150 mbar at therotary evaporator and the residue was purified by distillation (bp. 55°C. at 53 mbar) to give the methanesulfinic chloride (144.3 g, 1.46 mol,86.6% yield) as a light yellow liquid.

Step 2: To a solution of prop-2-en-1-amine (17.4 g, 22.9 ml, 304 mmol,Eq: 3.00) in diethyl ether (312 ml) was added at −78° C. a solution ofmethanesulfinic chloride (10 g, 101 mmol, Eq: 1.00) in diethyl ether(37.5 ml) dropwise. The reaction mixture was allowed to warm up to 0° C.and was stirred for 1 h to give a suspension. To the suspension wereadded three spoons of Na₂SO₄, filtered and evaporated to giveN-allylmethanesulfinamide (10.73 g, 90.0 mmol, 88.7% yield) as acolorless liquid which was used without further purification. MS (ESI):m/z=120.0 [M+H]⁺.

Synthesis of the Intermediate sulfinamide B4 B4a:2-[(2,4-dimethoxyphenyl)methyl]-1-methyl-1λ⁶-thia-2,7-diazacyclohept-7-ene1-oxide

Step 1: To a solution of 2,4-dimethoxybenzaldehyde (7.86 g, 47.3 mmol,Eq: 1.00) and prop-2-en-1-amine (3.24 g, 4.26 ml, 56.8 mmol, Eq: 1.2) in1,2-dichloroethane (100 ml) was added at 23° C. sodiumtriacetoxyborohydride (18.0 g, 85.1 mmol, Eq: 1.8) portionwise. Theresulting mixture was stirred at 23° C. for 16 hours. The reactionmixture was extracted with 1 N NaOH and DCM twice. The combined organicextracts were dried over Na₂SO₄, filtered and evaporated to give acolorless oil (12.5 g, 128%). The residue was purified by chromatography(70 g silica gel, 0-100% ethyl acetate in heptane) to giveN-(2,4-dimethoxybenzyl)prop-2-en-1-amine (6.1 g, 29.4 mmol, 62.2% yield)as a colorless oil. MS (ESI): m/z=208.1 [M+H]⁺.

Step 2: To a solution of N-allylmethanesulfinamide (4 g, 33.6 mmol, Eq:1.00) in dichloromethane (270 ml) was added in the dark at −78° C.tert-butyl hypochlorite (3.83 g, 3.99 ml, 35.2 mmol, Eq: 1.05) (1.91 g,1.99 ml, 17.6 mmol, Eq: 1.05). After stirring at −78° C. for 30 min asolution of N-(2,4-dimethoxybenzyl)prop-2-en-1-amine (8.35 g, 40.3 mmol,Eq: 1.2) and triethylamine (5.09 g, 7.02 ml, 50.3 mmol, Eq: 1.5) indichloromethane (90.0 ml) was dropwise added within 10 min. The coolingbath was removed and the mixture was stirred while warming up to ambienttemperature. After 2 h the mixture was poured onto 1 M HCl and extractedtwice with DCM. The combined organic layers were dried over Na₂SO₄,filtered and evaporated to give the crudeN,N′-diallyl-N-(2,4-dimethoxybenzyl)methanesulfonimidamide (10.67 g,32.9 mmol, 98.0% yield) which was used without further purification. MS(ESI): m/z=325.2 [M+H]⁺.

Step 3: To a solution ofN,N′-diallyl-N-(2,4-dimethoxybenzyl)methanesulfonimidamide (10.67 g,32.9 mmol, Eq: 1.00) in dichloromethane (400 ml) was added under argontricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene]ruthenium(II) (Grubbs II, Grubbs 2^(nd) generation catalyst) (96.8 mg, 114 μmol,Eq: 0.05). The reaction mixture was stirred at reflux (50° C. oilbath)for 2 hours. The mixture was evaporated and the residue was purified bycolumn chromatography (200 g silica gel, 0-10% methanol in ethylacetate) to give2-[(2,4-dimethoxyphenyl)methyl]-1-methyl-1λ⁶-thia-2,7-diazacyclohepta-4,7-diene1-oxide (6.25 g, 21.1 mmol, 64.1% yield) as a brown oil. MS (ESI):m/z=297.2 [M+H]⁺.

Step 4: To a solution of2-[(2,4-dimethoxyphenyl)methyl]-1-methyl-1λ⁶-thia-2,7-diazacyclohepta-4,7-diene1-oxide (6.25 g, 21.1 mmol, Eq: 1.00) in ethyl acetate (350 ml) wasadded under argon 10% Pd/C (1.12 g, 1.05 mmol, Eq: 0.05). The blacksuspension was set under hydrogen and was stirred for 2 hours. Addedagain 700 mg of 10% Pd/C and was stirred again for 1 h. Then thesuspension was set again under argon and the reaction mixture wasfiltered and evaporated to give. The crude material was purified byflash chromatography (50 g silica gel, 0-20% methanol in ethyl acetate)to give2-[(2,4-dimethoxyphenyl)methyl]-1-methyl-1λ⁶-thia-2,7-diazacyclohept-7-ene1-oxide (6.18 g, 20.7 mmol, 98.2% yield) as a brown oil. MS (ESI):m/z=299.3 [M+H]⁺.

Synthesis of the Intermediates A5 A5a (R³=Me):2-Methyl-propane-2-sulfinic acid{(R)-1-(6-bromo-3-fluoro-4-triethylsilyl-pyridin-2-yl)-2-[(R/S)-2-(2,4-dimethoxy-benzyl)-1-oxo-3,4,5,6-tetrahydro-2H-1λ⁶-[1,2,7]thiadiazepin-1-yl]-1-methyl-ethyl}-amide

To a solution of2-[(2,4-dimethoxyphenyl)methyl]-1-methyl-1λ⁶-thia-2,7-diazacyclohept-7-ene1-oxide (1.92 g, 6.43 mmol, Eq: 2.0) in tetrahydrofuran (30 ml) at −75°C. was dropwise added n-BuLi (1.6 M in hexane) (3.98 ml, 6.37 mmol, Eq:1.98). The clear solution was stirred at −50° C. for 2 hours. Then asolution of(R,E)-N-(1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide(1.4 g, 3.21 mmol, Eq: 1.00) in tetrahydrofuran (10 ml) was added at−75° C. dropwise. The reaction mixture was stirred at −50° C. for 3hours, and quenched at −75° C. with 10 ml of sat. NH₄Cl-sol. and 30 mlof water, followed by extraction with ethyl acetate (2×50 ml). Thecombined organic extracts were dried over Na₂SO₄, filtered andevaporated to give orange oil. The residue was purified by flashchromatography (50 g silica gel, 0-80% EtOAc in heptane) to give the2-methyl-propane-2-sulfinic acid{(R)-1-(6-bromo-3-fluoro-4-triethylsilyl-pyridin-2-yl)-2-[(R/S)-2-(2,4-dimethoxy-benzyl)-1-oxo-3,4,5,6-tetrahydro-2H-1λ⁶-[1,2,7]thiadiazepin-1-yl]-1-methyl-ethyl}-amideas a 1:1 mixture of 2 epimers. MS (ESI): m/z=733.2; 735.4 [M+H]⁺.

A5b (R³=CH₂F): 2-Methyl-propane-2-sulfinic acid{(S)-1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-1-[(S/R)-2-(2,4-dimethoxy-benzyl)-1-oxo-3,4,5,6-tetrahydro-2H-1λ⁶-[1,2,7]thiadiazepin-1-ylmethyl]-2-fluoro-ethyl}-amide

Prepared from2-[(2,4-dimethoxyphenyl)methyl]-1-methyl-1λ⁶-thia-2,7-diazacyclohept-7-ene1-oxide (2.6 g, 8.71 mmol, Eq: 1.98) and(R,E)-N-(1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide(2 g, 4.41 mmol, Eq: 1.00) according to the procedure described forintermediate A5a to give the 2-methyl-propane-2-sulfinic acid{(S)-1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-1-[(S/R)-2-(2,4-dimethoxy-benzyl)-1-oxo-3,4,5,6-tetrahydro-2H-1λ⁶-[1,2,7]thiadiazepin-1-ylmethyl]-2-fluoro-ethyl}-amide(440 mg, 585 μmol, 13.3% yield) as a yellow solid as a 1:1 mixture of 2epimers. MS (ESI): m/z=751.2; 753.3 [M+H]⁺.

Synthesis of the Intermediates A6 A6a (R³=Me):2-Methyl-propane-2-sulfinic acid{(R)-1-(6-bromo-3-fluoro-pyridin-2-yl)-2-[(R/S)-2-(2,4-dimethoxy-benzyl)-1-oxo-3,4,5,6-tetrahydro-2H-1λ⁶-[1,2,7]thiadiazepin-1-yl]-1-methyl-ethyl}-amide

To a solution of 2-methyl-propane-2-sulfinic acid{(R)-1-(6-bromo-3-fluoro-4-triethylsilyl-pyridin-2-yl)-2-[(R/S)-2-(2,4-dimethoxy-benzyl)-1-oxo-3,4,5,6-tetrahydro-2H-1λ⁶-[1,2,7]thiadiazepin-1-yl]-1-methyl-ethyl}-amide(3.82 g, 5.2 mmol, Eq: 1.00) in tetrahydrofuran (50 ml) and DMF (10 ml)was added at 23° C. acetic acid (313 mg, 298 μl, 5.21 mmol, Eq: 1.0) anddry potassium fluoride (302 mg, 5.21 mmol, Eq: 1.0). The reactionmixture was stirred at 23° C. for 3 hours. The reaction mixture wasevaporated, then extracted twice with ethyl acetate/NaHCO₃, washed theorganic layers with brine, dried over Na₂SO₄, filtered and evaporated tothe crude 2-methyl-propane-2-sulfinic acid{(R)-1-(6-bromo-3-fluoro-pyridin-2-yl)-2-[(R/S)-2-(2,4-dimethoxy-benzyl)-1-oxo-3,4,5,6-tetrahydro-2H-1λ⁶-[1,2,7]thiadiazepin-1-yl]-1-methyl-ethyl}-amide(2.88 g, 4.64 mmol, 89.3% yield) as a 1:1 mixture of epimers which wasused without further purification. MS (ESI): m/z=619.3; 621.5 [M+H]⁺.

A6b (R³=CH₂F): 2-Methyl-propane-2-sulfinic acid{(S)-1-(6-bromo-3-fluoro-pyridin-2-yl)-2-[(S/R)-2-(2,4-dimethoxy-benzyl)-1-oxo-3,4,5,6-tetrahydro-2H-1λ⁶-[1,2,7]thiadiazepin-1-ylmethyl]-2-fluoro-ethyl}-amide

Prepared from 2-methyl-propane-2-sulfinic acid{(S)-1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-1-[(S/R)-2-(2,4-dimethoxy-benzyl)-1-oxo-3,4,5,6-tetrahydro-2H-1λ⁶-[1,2,7]thiadiazepin-1-ylmethyl]-2-fluoro-ethyl}-amide(780 mg, 1.04 mmol, Eq: 1.00) according to the procedure described forintermediate Aha to give the 2-methyl-propane-2-sulfinic acid{(S)-1-(6-bromo-3-fluoro-pyridin-2-yl)-2-[(S/R)-2-(2,4-dimethoxy-benzyl)-1-oxo-3,4,5,6-tetrahydro-2H-1λ⁶-[1,2,7]thiadiazepin-1-ylmethyl]-2-fluoro-ethyl}-amide(660 mg, 1.04 mmol, 99.8% yield) as a light yellow oil as a 1:1 mixtureof epimers which was used without further purification. MS (ESI):m/z=637.2; 639.5 [M+H]⁺.

Synthesis of the Intermediates A7 A7a (R³=Me):(2R)-2-(6-bromo-3-fluoropyridin-2-yl)-1-[(1R/S)-1-oxo-1λ⁶-thia-2,7-diazacyclohept-7-en-1-yl]propan-2-amine

To a solution of 2-methyl-propane-2-sulfinic acid{(R)-1-(6-bromo-3-fluoro-pyridin-2-yl)-2-[(R/S)-2-(2,4-dimethoxy-benzyl)-1-oxo-3,4,5,6-tetrahydro-2H-1λ⁶-[1,2,7]thiadiazepin-1-yl]-1-methyl-ethyl}-amide(2.88 g, 4.64 mmol, Eq: 1.0) in THF (10 ml) was added at 23° C. HCl (4 Nin dioxane) (1.74 ml, 6.97 mmol, Eq: 1.5). After stirring for 1 h thereaction mixture was evaporated. Then TFA (26.5 g, 17.9 ml, 232 mmol,Eq: 100) was added and stirring continued at 23° C. for 18 h. The darkred reaction solution was evaporated, extracted with sat.NaHCO₃-sol./ethyl acetate, washed the organic layers with brine, driedover Na₂SO₄, filtered and evaporated. The residue was purified by flashchromatography (20 g silica gel, 0-10% MeOH in CH₂Cl₂) to give the(2R)-2-(6-bromo-3-fluoropyridin-2-yl)-1-[(1R/S)-1-oxo-1λ⁶-thia-2,7-diazacyclohept-7-en-1-yl]propan-2-amine(700 mg, 1.92 mmol, 82.5% yield) as a light brown solid (1:1 mixture ofepimers). MS (ESI): m/z=365.2; 367.4 [M+H]⁺.

A7b (R³=CH₂F):(2S)-2-(6-Bromo-3-fluoropyridin-2-yl)-1-fluoro-3-[(1S/R)-1-oxo-1λ⁶-thia-2,7-diazacyclohept-7-en-1-yl]propan-2-amine

Prepared from 2-methyl-propane-2-sulfinic acid{(S)-1-(6-bromo-3-fluoro-pyridin-2-yl)-2-[(S/R)-2-(2,4-dimethoxy-benzyl)-1-oxo-3,4,5,6-tetrahydro-2H-1λ⁶-[1,2,7]thiadiazepin-1-ylmethyl]-2-fluoro-ethyl}-amide(650 mg, 1.02 mmol, Eq: 1.00) according to the procedure described forintermediate Ala to give the(2S)-2-(6-bromo-3-fluoropyridin-2-yl)-1-fluoro-3-[(1S/R)-1-oxo-1λ⁶-thia-2,7-diazacyclohept-7-en-1-yl]propan-2-amine(320 mg, 835 μmol, 81.9% yield) as a white solid (1:1 mixture ofepimers). MS (ESI): m/z=383.2; 385.4 [M+H]⁺.

Synthesis of the Intermediates A8 and A9 A9a (R³=Me):N-[(3R,4aR)-3-(6-Bromo-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-benzamideA9b (R³=Me):N-[(3R,4aS)-3-(6-Bromo-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-benzamide

Step 1: To a solution of a mixture of(R)-1-(6-Bromo-3-fluoro-pyridin-2-yl)-1-methyl-2-((R/S)-1-oxo-3,4,5,6-tetrahydro-2H-1λ⁶-[1,2,7]thiadiazepin-1-yl)-ethylamine(690 mg, 1.89 mmol, Eq: 1.00) in tetrahydrofuran (34.5 ml) was added at23° C. benzoyl isothiocyanate (339 mg, 279 μl, 2.08 mmol, Eq: 1.1).After stirring for 1 hour at 23° C. the light yellow solution wasevaporated to give the intermediate thiourea A8a/b which was useddirectly in the next step.

Step 2: The intermediate thiourea A8a/b from step 1 was dissolved inacetonitrile (34.5 ml) and EDC.HCl (543 mg, 2.83 mmol, Eq: 1.5) wasadded and the reaction mixture was stirred at 80° C. for 2 hours. Thelight yellow solution was evaporated and the residue was directlypurified by chromatography (20 g silica gel, 0-50% EtOAc in heptane) togiveN-[(3R,4aR)-3-(6-bromo-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-benzamide(240 mg, 485 μmol, 25.7% yield) as the faster eluting isomer andN-[(3R,4aS)-3-(6-bromo-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-benzamide(220 mg, 445 μmol, 23.6% yield) as the slower eluting isomer. MS (ESI):m/z=494.3; 496.2 [M+H]⁺.

A9c (R³=CH₂F):N-[(1R/S,10S)-10-(6-bromo-3-fluoropyridin-2-yl)-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]benzamide

Prepared in two steps from(2S)-2-(6-bromo-3-fluoropyridin-2-yl)-1-fluoro-3-[(1S/R)-1-oxo-1λ⁶-thia-2,7-diazacyclohept-7-en-1-yl]propan-2-amine(320 mg, 835 μmol, Eq: 1.00) according to the procedure described forintermediates A9a/b to give theN-[(1R/S,10S)-10-(6-bromo-3-fluoropyridin-2-yl)-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]benzamide(332 mg, 648 μmol, 77.6% yield) as a white foam (1:1 mixture ofepimers). MS (ESI): m/z=512.2; 514.3 [M+H]⁺.

Synthesis of the Intermediates A10 A10a (R³=Me):(3R,4aR)-3-(6-Bromo-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-carbamicacid tert-butyl ester

Step 1: To a solution ofN-[(3R,4aR)-3-(6-bromo-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-benzamide(230 mg, 465 μmol, Eq: 1.00) in tetrahydrofuran (4 ml) was added at 23°C. triethylamine (104 mg, 143 μl, 1.02 mmol, Eq: 2.2) and DMAP (11.4 mg,93.0 μmol, Eq: 0.2) followed by the addition of Boc₂O (223 mg, 1.02mmol, Eq: 2.2). The reaction mixture was stirred at 23° C. for 4 hours.Evaporated all volatiles to give the intermediate N-Boc/N-benzoylcompound which was used directly in the next step.

Step 2: The intermediate N-Boc/N-benzoyl compound from step 1 wasdissolved in methanol (2 ml) and ammonia (7 N in methanol) (1.66 ml,11.6 mmol, Eq: 25) was added and the mixture was stirred at 23° C. for30 min. Evaporation of all volatiles and the residue was purified bychromatography (20 g silica gel, 0-50% EtOAc in heptane) to give(3R,4aR)-3-(6-bromo-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-A-carbamicacid tert-butyl ester (168 mg, 343 μmol, 73.6% yield) as a white foam.MS (ESI): m/z=490.1; 492.2 [M+H]⁺.

A10b (R³=Me):(3R,4aS)-3-(6-Bromo-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-carbamicacid tert-butyl ester

Step 1: To a solution ofN-[(3R,4aS)-3-(6-bromo-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-benzamide(253 mg, 512 μmol, Eq: 1.00) in tetrahydrofuran (4 ml) was added at 23°C. triethylamine (114 mg, 157 μl, 1.13 mmol, Eq: 2.2) and DMAP (12.5 mg,102 μmol, Eq: 0.2) followed by the addition of Boc₂O (246 mg, 1.13 mmol,Eq: 2.2). The reaction mixture was stirred at 23° C. for 4 hours.Evaporated all volatiles to give the intermediate N-Boc/N-benzoylcompound which was used directly in the next step.

Step 2: The intermediate N-Boc/N-benzoyl compound from step 1 wasdissolved in methanol (2 ml) and ammonia (7 N in methanol) (1.66 ml,11.6 mmol, Eq: 25) was added and the mixture was stirred at 23° C. for30 min. Evaporation of all volatiles and the residue was purified bychromatography (20 g silica gel, 0-50% EtOAc in heptane) to give(3R,4aS)-3-(6-bromo-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-A-carbamicacid tert-butyl ester (213 mg, 434 μmol, 84.9% yield) as a white foam.MS (ESI): m/z=490.1; 492.2 [M+H]⁺.

A10c (R³=CH₂F): tert-butylN-[(1R/S,10S)-10-(6-bromo-3-fluoropyridin-2-yl)-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]carbamate

Prepared fromN-[(1R/S,10S)-10-(6-bromo-3-fluoropyridin-2-yl)-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]benzamide(328 mg, 640 μmol, Eq: 1.00) according to the procedure described forintermediates A10 to give the tert-butylN-[(1R/S,10S)-10-(6-bromo-3-fluoropyridin-2-yl)-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]carbamate(242 mg, 476 μmol, 74.4% yield) as a white foam (1:1 mixture ofepimers). MS (ESI): m/z=508.3; 510.2 [M+H]⁺.

Synthesis of the Intermediate Boc-aminopyridine A11 A11a (R³=Me):[(3R,4aR)-3-(6-Amino-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-carbamicacid tert-butyl ester

To a solution of(3R,4aR)-3-(6-bromo-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-carbamicacid tert-butyl ester (167 mg, 341 μmol, Eq: 1.00) in dioxane (3.00 ml)and water (1.00 ml) was added at 23° C. sodium azide (177 mg, 2.72 mmol,Eq: 8.0) followed by the addition of copper(I) iodide (25.9 mg, 136μmol, Eq: 0.4), sodium L-ascorbate (13.5 mg, 68.1 μmol, Eq: 0.2) andfinally trans-N,N′-dimethylcyclohexane-1,2-diamine (29.1 mg, 32.2 μl,204 μmol, Eq: 0.6). The dark reaction mixture was stirred at 70° C. for30 min. The dark green reaction mixture was quenched with sat.NaHCO₃-sol., then extracted twice with ethyl acetate. The combinedorganic layers were dried over Na₂SO₄, filtered and evaporated to give abrown oil, which was purified by flash chromatography (10 g silica gel;0-100% ethyl acetate in heptane) to give[(3R,4aR)-3-(6-amino-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-carbamicacid tert-butyl ester (36 mg, 84.4 μmol, 24.8% yield) as a light yellowfoam. MS (ESI): m/z=427.4 [M+H]⁺.

A11b (R³=Me):[(3R,4aS)-3-(6-Amino-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-carbamicacid tert-butyl ester

To a solution of(3R,4aS)-3-(6-bromo-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-carbamicacid tert-butyl ester (213 mg, 434 μmol, Eq: 1.00) in dioxane (3.00 ml)and water (1.00 ml) was added at 23° C. sodium azide (226 mg, 3.47 mmol,Eq: 8.0) followed by the addition of copper(I) iodide (33.1 mg, 174μmol, Eq: 0.4), sodium L-ascorbate (17.2 mg, 86.9 μmol, Eq: 0.2) andfinally trans-N,N′-dimethylcyclohexane-1,2-diamine (37.1 mg, 41.1 μl,261 μmol, Eq: 0.6). The dark reaction mixture was stirred at 70° C. for1 h. The dark green reaction mixture was quenched with sat. NaHCO₃-sol.,then extracted twice with ethyl acetate. The combined organic layerswere dried over Na₂SO₄, filtered and evaporated to give a brown oil,which was purified by flash chromatography (10 g silica gel; 0-20%methanol in dichloromethane) to give[(3R,4aS)-3-(6-amino-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-carbamicacid tert-butyl ester (154 mg, 307 μmol, 70.7% yield) as an off-whitesolid. MS (ESI): m/z=427.4 [M+H]⁺.

A11c (R³=CH₂F): tert-butylN-[(1S,10S)-10-(6-amino-3-fluoropyridin-2-yl)-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]carbamateA11d (R³=CH₂F): tert-butylN-[(1R,10S)-10-(6-amino-3-fluoropyridin-2-yl)-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]carbamate

Prepared from to give the tert-butylN-[(1R/S,10S)-10-(6-bromo-3-fluoropyridin-2-yl)-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]carbamate(242 mg, 476 μmol, Eq: 1.00) according to the procedure described forintermediates A11 to give the faster eluting isomer tert-butylN-[(1S,10S)-10-(6-amino-3-fluoropyridin-2-yl)-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]carbamate(61 mg, 137 μmol, 28.8% yield) as a white foam and the slower elutingisomer tert-butylN-[(1R,10S)-1046-amino-3-fluoropyridin-2-yl)-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]carbamate(76 mg, 171 μmol, 35.9% yield) as a light yellow solid. MS (ESI):m/z=445.4 [M+H]⁺.

Synthesis of the Intermediate Boc-amides A12 Deprotected amides I

General Procedure for the Coupling of the Boc-aminopyridines A11 withthe acid to the Boc-amide A12

T3P-Method: To a solution of the Boc-aminopyridine A11 (0.10 mmol) andthe acid (0.2 mmol) in EtOAc (1.2 ml) was added at 22° C. T3P (50% inEtOAc, 0.09 ml, 0.15 mmol) and stirring was continued 2 h. A furtherportion of T3P (0.05 ml, 0.08 mmol) was added and stirring was continuedfor 2 h. The mixture was partitioned between saturated aqueous NaHCO₃and EtOAc, the organic layer was dried, evaporated and the residuepurified by flash chromatography (SiO₂, gradient of EtOAc in heptane) togive the Boc-amide A12.

Ghosez's Reagent Method: To a suspension of the acid (197 μmol, Eq: 1.5)in dry dichloromethane (1.5 ml) at 0° C. was dropwise added1-chloro-N,N,2-trimethylpropenylamine (Ghosez's reagent) (52.8 mg, 395μmol, Eq: 3) and the mixture was stirred at 0° C. for 1 hour. Thismixture was then added to a solution of the Boc-aminopyridine A11 (132μmol, Eq: 1.00) and diisopropylethylamine (51.0 mg, 69.0 μl, 395 μmol,Eq: 3) in dry dichloromethane (1.5 ml) at 0° C. The ice bath was removedand the mixture was stirred 1 to 16 hour(s) at ambient temperature.Evaporated totally at ambient temperature and directly purified by flashchromatography (silica gel, gradient of EtOAc in heptane) to give theBoc-amide A12.

General Procedure for the Deprotection of the Boc-amide A12 to the amideI

To a solution of the Boc-amide A12 (0.04 mmol) in dichloromethane (0.5ml) was added at 22° C. trifluoroacetic acid (1.2 mmol) and stirring wascontinued for 16 h. The mixture was evaporated, the residue diluted withEtOAc and evaporated again. The residue was triturated with diethylether/pentane, the suspension was filtered and the residue dried to givethe amide I. Alternative workup to obtain the free base: after stirringfor 16 h, all volatiles were removed in vacuum, the residue waspartitioned between EtOAc and sat. NaHCO₃-sol., the organic layer waswashed with brine and dried over Na₂SO₄. Filtration and removal of thesolvent in vacuum left the crude product which was purified by flashchromatography to give the amide I.

A12a (R³=Me):43R,4aR)-3-{6-[(5-Cyano-pyridine-2-carbonyl)-amino]-3-fluoro-pyridin-2-yl}-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl)-carbamicacid tert-butyl ester

[(3R,4aR)-3-(6-Amino-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-carbamicacid tert-butyl ester A11a (28 mg, 65.6 μmol) was coupled with5-cyanopicolinic acid according to the Ghosez's reagent-method to givethe title compound (64 mg, 69.0 μmol, 105% yield) as a yellow oil whichwas used without further purification. MS (ESI): m/z=557.5 [M+H]⁺.

A12b (R³=Me):((3R,4aS)-3-{6-[(5-Cyano-pyridine-2-carbonyl)-amino]-3-fluoro-pyridin-2-yl}-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl)-carbamicacid tert-butyl ester

[(3R,4aS)-3-(6-Amino-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-carbamicacid tert-butyl ester A11b (71 mg, 166 μmol) was coupled with5-cyanopicolinic acid according to the Ghosez's reagent-method to giveafter flash chromatography (SiO₂, gradient of MeOH in DCM, 0 to 20%MeOH) the title compound (144 mg, 186 μmol, 112% yield) as a yellow oilwhich was used without further purification. MS (ESI): m/z=557.4 [M+H]⁺.

A12c (R³=Me):43R,4aS)-3-{16-[(5-Cyano-3-methyl-pyridine-2-carbonyl)-amino]-3-fluoro-pyridin-2-yl}-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl)-carbamicacid tert-butyl ester

[(3R,4aS)-3-(6-Amino-3-fluoro-pyridin-2-yl)-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl]-carbamicacid tert-butyl ester A11b (35 mg, 82.1 μmol) was coupled with5-cyano-3-methylpicolinic acid according to the Ghosez's reagent-methodto give the crude title compound (70 mg, 85.9 μmol, 105% yield) as ayellow oil which was used without further purification. MS (ESI):m/z=571.3 [M+H]⁺.

A12d (R³=CH₂F): tert-butylN-[(1S,10S)-10-[6-[(5-cyanopyridine-2-carbonyl)amino]-3-fluoropyridin-2-yl]-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]carbamate

tert-ButylN-[(1S,10S)-10-(6-amino-3-fluoropyridin-2-yl)-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]carbamateA11c (61 mg, 137 μmol) was coupled with 5-cyanopicolinic acid accordingto the Ghosez's reagent-method to give after flash chromatography(silica gel, 10 g, 0-80% EtOAc in heptane) the title compound (39 mg,67.9 μmol, 49.5% yield) as a light yellow foam. MS (ESI): m/z=575.5[M+H]⁺.

A12e (R³=CH₂F): tert-butylN-[(1R,10S)-10-[6-[(5-cyanopyridine-2-carbonyl)amino]-3-fluoropyridin-2-yl]-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]carbamate

tert-ButylN-[(1R,10S)-10-(6-amino-3-fluoropyridin-2-yl)-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]carbamateA11d (76 mg, 171 μmol) was coupled with 5-cyanopicolinic acid accordingto the Ghosez's reagent-method to give after flash chromatography(silica gel, 10 g, 0-80% EtOAc in heptane) the title compound (84 mg,146 μmol, 85.5% yield) as a yellow foam. MS (ESI): m/z=575.5 [M+H]⁺.

EXAMPLE 1 5-Cyano-pyridine-2-carboxylic acid[6-((3R,4aR)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amide

((3R,4aR)-3-{16-[(5-Cyano-pyridine-2-carbonyl)-amino]-3-fluoro-pyridin-2-yl}-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl)-carbamicacid tert-butyl ester (60 mg, 64.7 μmol, Eq: 1.00) was deprotected withTFA in DCM to give after flash chromatography (SiO₂, 5 g, 0-10% MeOH inEtOAc) the title compound (12 mg, 26.3 μmol, 40.6% yield) as a lightbrown solid. MS (ISP): m/z=457.2 [(M+H)⁺].

EXAMPLE 2 5-Cyano-pyridine-2-carboxylic acid[6-((3R,4aS)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amide

((3R,4aS)-3-{16-[(5-Cyano-pyridine-2-carbonyl)-amino]-3-fluoro-pyridin-2-yl}-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl)-carbamic acid tert-butyl ester (144 mg, 186 μmol, Eq:1.00) was deprotected with TFA in DCM to give after flash chromatography(SiO₂, 5 g, 0-10% MeOH in EtOAc+DCM/MeOH/NH₄OH 110:10:1) the titlecompound (53 mg, 116 μmol, 62.3% yield) as an off-white solid. MS (ISP):m/z=457.3 [(M+H)⁺].

EXAMPLE 3 5-Cyano-3-methyl-pyridine-2-carboxylic acid[6-((3R,4aS)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amide

((3R,4aS)-3-{16-[(5-Cyano-3-methyl-pyridine-2-carbonyl)-amino]-3-fluoro-pyridin-2-yl}-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-1-yl)-carbamicacid tert-butyl ester (70 mg, 85.9 μmol, Eq: 1.00) was deprotected withTFA in DCM to give after flash chromatography (SiO₂, 10 g, 0-10% MeOH inEtOAc+DCM/MeOH/NH₄OH 110:10:1) the title compound (18 mg, 38.3 μmol,44.6% yield) as a light brown foam. MS (ISP): m/z=471.3 [(M+H)⁺].

EXAMPLE 4N-[6-[(1S,10S)-8-Amino-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide

tert-ButylN-[(1S,10S)-10-[6-[(5-cyanopyridine-2-carbonyl)amino]-3-fluoropyridin-2-yl]-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]carbamate(39 mg, 67.9 μmol, Eq: 1.00) was deprotected with TFA in DCM to giveafter flash chromatography (SiO₂, 5 g, 0-10% MeOH inEtOAc+DCM/MeOH/NH₄OH 110:10:1) the title compound (8.5 mg, 17.9 μmol,26.4% yield) as an off white solid. MS (ISP): m/z=475.2 [(M+H)⁺].

EXAMPLE 5N-[6-[(R1R,10S)-8-Amino-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide

tert-ButylN-[(1R,10S)-10-[6-[(5-cyanopyridine-2-carbonyl)amino]-3-fluoropyridin-2-yl]-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-8-yl]carbamate(84 mg, 146 μmol, Eq: 1.00) was deprotected with TFA in DCM to giveafter flash chromatography (SiO₂, 5 g, 0-10% MeOH inEtOAc+DCM/MeOH/NH₄OH 110:10:1) the title compound (42 mg, 88.5 μmol,60.5% yield) as a light yellow foam. MS (ISP): m/z=475.2 [(M+H)⁺].

The invention claimed is:
 1. A pharmaceutical composition, comprising acompound, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier and/or a pharmaceutically acceptableauxiliary substance, wherein said compound is selected from the groupconsisting of: 5-Cyano-pyridine-2-carboxylic acid[6-((3R,4aS)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-n-2-yl]-amide,N-[6-[(1S,10S)-8-Amino-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide,5-Cyano-3-methyl-pyridine-2-carboxylic acid[6-((3R,4aS)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amide,5-Cyano-pyridine-2-carboxylic acid[6-((3R,4aR)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amide,N-[6-[(1R,10S)-8-Amino-10-(difluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.40]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide,N-[6-[(1R,10S)-8-Amino-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide,andN-[6-[(1S,10S)-8-Amino-10-(difluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide.2. A method of treating Alzheimer's disease, comprising the step ofadministering a therapeutically effective amount of a compound, or apharmaceutically acceptable salt thereof, to a human being or animal inneed thereof, wherein said compound is selected from the groupconsisting of: 5-Cyano-pyridine-2-carboxylic acid[6-((3R,4aS)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amide,N-[6-[(1S,10S)-8-Amino-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.40]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide,5-Cyano-3-methyl-pyridine-2-carboxylic acid[6-((3R,4aS)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amide,5-Cyano-pyridine-2-carboxylic acid [6-((3R,4aR)-1-amino-3-methyl-4a-oxo-3,4,6,7,8,9-hexahydro-4aλ⁶-thia-2,5,9a-triaza-benzocyclohepten-3-yl)-5-fluoro-pyridin-2-yl]-amide,N-[6-[(1R10S)-8-Amino-10-(difluoronnethyl)-1-oxo-1λ⁶-thia-2,7,9-trazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide,N-[6-[(1R, 10S)-8-Amino-10-(fluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabioyclo [5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide, andN-[6-[(1S,10S)-8-Amino-10-(difluoromethyl)-1-oxo-1λ⁶-thia-2,7,9-triazabicyclo[5.4.0]undeca-1,8-dien-10-yl]-5-fluoropyridin-2-yl]-5-cyanopyridine-2-carboxamide.